4-oxa-3-keto-delta**1-pregnene derivatives

ABSTRACT

THIS DISCLOSES, AS NEW COMPOUNDS, 4-OXA-3-KETO-$1PREGNENE STEROIDS INCLUDING THE 19-NOR DERIVATIVES AND THOSE CONTAINING OPITIONAL SUBSTITUTIONS AT POSITIONS C-16 AND C-17A. THESE COMPOUNDS ARE PROGESTATIONAL AGENTS, HAVE ANTI-ANDROGENIC, ANTI-GONADOTROPHIC, AND ESTROGENIC PROPERTIES AND ARE USEFUL IN FERTILITY CONTROL, IN THE TREATMENT OF PREMENSTRAUAL TENSIONS, IN LOWERING BLOOD CHOLESTEROL LEVELS, AND IN THE TREATMENT OF ACNE, BENIGN PROSTATE HYPERTROPHY AND HIRSUTISM. ALSO DISCLOSED ARE METHODS AND IMTERMEDIATES USEFUL FOR THE PREPARATION OF THESE COMPOUNDS.

United States Patent 3,644,421 4-0XA-3-KET0-A -PREGNENE DERIVATIVESAlexander D. Cross, Mexico City, Mexico, assignor to Syntex Corporation,Panama, Panama No Drawing. Continuation-impart of application Ser. No.411,554, Nov. 16, 1964, now Patent No. 3,417,106. This application Dec.2, 1968, Ser. No. 780,580

Int. Cl. C07d 19/00 US. Cl. 260-3405 8 Claims ABSTRACT OF THE DISCLOSUREThis discloses, as new compounds, 4-oxa-3-keto-A pregnene steroidsincluding the l9-nor derivatives and those containing optionalsubstitutions at positions C-16 and C-l7u. These compounds areprogestational agents, have anti-androgenic, anti-gonadotrophic, andestrogenic properties and are useful in fertility control, in thetreatment of premenstrual tensions, in lowering blood cholesterollevels, and in the treatment of acne, benign prostate hypertrophy andhirsutism. Also disclosed are methods and intermediates useful for thepreparation of these compounds.

This is a continuation-in-part of application Ser. No. 411,554, filedNov. 16, 1964, now US. Pat. 3,417,106.

This invention relates to novel cyclopentanopolyhydrophenanthrenederivatives and to processes for the preparation thereof.

More particularly, this invention relates to novel 3,20- diketo-4-oxa-A-uand SB-pregnenes (including 19-nor- A -pregnenes) represented by thegeneral Formula V:

In this and succeeding formulas, R represents hydrogen or methyl, Rrepresents hydrogen, hydroxy, or acyloxy, T represents hydrogen,a-hydroxy, a-acyloxy, a-methyl, or fl-methyl, with T being other thana-hydroxy or u-acyloxy when R represents hydrogen, and R and T takentogether represent the grouping wherein R represents lower alkyl orlower aryl containing up to eight carbon atoms, inclusive, and Rrepresents hydrogen or lower al-kyl.

One particular group of important compounds hereof are the C-l7aoxygenated derivatives, that is, those compounds depicted by Formula Vabove wherein R is other than hydrogen.

In the present specification and claims, the term lower alkyl and loweraryl denote alkyl and aryl groups containing up to eight carbon atoms.Examples of such includes methyl, ethyl, propyl, butyl, pentyl, hexyl,phenyl, tolyl, xylyl, benzyl, and so forth. The term acyloxy refers toacyloxy groups which are derived from carboxylic acids containing lessthan 12 carbon atoms. These acids can be saturated or unsaturated(including aromatic), and can be straight or branched chain, cyclic orcyclic-aliphatic. In addition, they can be unsubstituted or substitutedwith one or more functional groups, such as hydroxyl groups, alkoxygroups containing up to six carbon atoms, acyloxy groups containing upto 12 carbon atoms, nitro groups, amino groups and halogen 3,644,421Patented Feb. 22, 1972 atoms. Included among such ester groups areacetate, trimethylacetate, t-butylacetate, aminoacetate, phenoxyacetate,propionate, cyclopentylpropionate, B-chloropropionate,,B-chloropropionate, aminoacetate, caproate, enanthate, adamantoate,benzoate, bicyclo[2.2.2]oct-2-ene-lcarboxylate, bicyclo[2.2.2]octane 1carboxylate and 4-methylbicyclo[2.2.2]oct-2-ene-l-car boxylate groups.In the present specification and claim, the wavy lines appearing in thestructural formulas which connect the C-5 and C-16 carbon atoms to thehydrogen atom and T grouping, respectively, denote and include both thealpha (or) and beta Configurations.

The novel 3,20-diketo-4-oxa-A -5aand 5,8-pregnene and -l9-norpregnenederi'vatives represented by Formula V hereinabove are progestationalagents having oral activity. In addition, they have anti-androgenic,anti-estrogenic, anti-gonadotrophic and diuretic properties. They areaccordingly useful in fertility control, in the treatment ofpremenstrual tension and in lowering blood cholesterol levels. They arealso accordingly useful in the treatment of acne, benign prostatehypertrophy and hirsutism in females. In accordance with this utility,the compounds of the present invention are employed in the same manneras compounds having similar properties, such as progestrone,chlormadinone acetate, ethynyl estradiol, cyproterone acetate, and soforth. They can be administered by the usual routes, orally orparenterally, either alone or in conjunction with other medicinal agentsor in pharmaceutically acceptable non-toxic compositions formed by theincorporation of any of the normally employed excipients.

The novel compounds of the present invention are prepared by a processwhich can be illustrated schematically as follows:

In carrying out this process, the starting material (I) is reactedtogether with a stream of ozone. This reaction is conveniently conductedin an organic reaction medium. Suitable media include methylenedichloride, ethyl acetate (which can a contain trace or larger amountsof acetic acid), chloroform, and the like. This reaction is furtherconducted at from about C. to about 20 C. and preferably at about 70 C.and for a period of time sufficient to provide an excess of ozone in thereaction mixture. Following this period, the ozonized reaction mixtureis reacted with an aqueous 30% solution of hydrogen peroxide in anamount of from about 0.5% to about 5% by volume, preferably about 1% byvolume, based on the volume of the ozonized mixture, or with anequivalent amount of aqueous hydrogen peroxide solution of differentconcentration. This reaction is conducted at a temperature of from about20 C. to about 30 C., preferably room temperature (about 25 C.) for fromabout to about 40 hours. This described procedure provides thecorresponding 3,5-seco-5-on-3-oic acid intermediate (II).

Alternatively, when the starting material (I) does not contain a 160zora 17a-hydroxy or -acyloxy group (for example, R and T=hydrogen, or R+T=cycloalkylidenedioxy), the 3,5-seco-5-on-3-oic acid (II) can also beobtained by first reacting the starting material (I) with a strongoxidizing agent capable of attacking double bonds. Included among suchoxidizing agents are the alkali metal permanganates, for example,potassium permanganate, and the like, which, upon ionization, produceanions having a reduction potential in the order of, or greater than,+0.5 volt, with respect to their nearest reduced state. This reaction isconveniently conducted in neutral or weakly basic solution which can beprovided, for example, by aqueous potassium carbonate together with astrongly polar solvent, such as t-butanol, monoglyme, and the like.During this reaction, the reaction mixture is further treated with analkali metal perhalate, such as sodium periodate, sodium metaperiodate,potassium perchlorate, or the like. The ensuing reaction is conducted ata temperature of from 0 C. to about C. and for a period of timesufficient to produce the 3,5-seco-5-on-3- oic acid intermediate (II).

The thus-obtained 3,5-seco-5-on-3-oic acid (II) is reduced with analkali metal borohydride, such as sodium borohydride, or the like. Thisreaction is conveniently conducted in an organic ether, such as dioxane,tetrahydrofuran, and the like, at a temperature of from about 0 C. toabout C. for a period of time ranging from a few minutes to about 12 to24 hours, Upon reaction end the reaction mixture is acidified with astrong acid, for example, a strong mineral acid such as hydrochloricacid, or the like, preferably in an amount suificient to give a pH offrom about 1 to 4. Thus obtained is a mixture of the corresponding4-oxa-5a-pregnan-20a-ol-3-one, 4-oxa- 5fi-pregnan-20a-ol-3-one, 4oxa-5a-pregnan-20B-ol-3-one, and 4 oxa-SB-pregnan-ZOfi-ol-3-oneintermediates (III). These products can be separated into the individualisomers by fractional crystallization or standard chromatographictechniques. Alternatively, the mixture of 5- and 20-isomers, or alater-obtained mixture of 5aand 5,8- isomers, can be used as such in anysubsequent reactions and the product thereafter separated into theindividual isomers.

In the preparation of the corresponding A -derivatives (IV) of thepresent invention, the mixture of 5- and 20- isomers (III) or any andeach of them is reacted together with an excess, ranging upwards of atwo-fold or more molar excess, of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. This reaction is conveniently conducted in organic liquidreaction medium, such as dioxane, tetrahydrofuran, monoglyme, diglyme,and the like, and at the boiling point of the mixture and under refluxfor at least about 48 hours and preferably for not more than about 10days. Again a mixture of the 50,2Ooc, 5/3,20oc, 501,205, 513,206 isomersis obtained which can be respectively separated into the individualisomers in accordance with known procedures or utilized per se in thesubsequent process step.

The thus prepared intermediates (IV) is oxidized under substantiallyanhydrous conditions with a carbodiimide in a hydrocarbon sulfoxidemedium and in the presence of an acid catalyst. This reaction ispreferably conducted from about 10 C. to about 100 C., preferably atroom temperature, for from about minutes to about 48 hours. Suitablecarbodiimides include the N,N-di(hydrocarbon substituted)carbodiimdes,preferably an N,N'-dialkyl-(ineluding cycloalkyl)carb0diimide, forexample, N,N-dimethylcarbodiimidie, N,N'-di-n-propylcarbodiimide, N,N'-dibutylcarbodiimide, N,N dicyclohexylcarbodiimide, N,N-di(methylcyclohexyl carbodiimide, N,N-di-p-tolylcarbodiimide, and the like.The amount employed can range from 1 to about 10 molar equivalents permole equivalent of the 20-hydroxy compound. Suitable hydrocarbonsulfoxides include dimethylsulfoxide, diethylsulfoxide,tetramethylenesulfoxide, and the like. These can be used alone or inadmixture with one or more mutually compatible inert organic solvent,such as benzene, toluene, xylene, dioxane, ethyl acetate, and the like.The acid catalyst for this reaction is employed in amounts of from about0.01 to about 5 molar equivalents per mole of 20- hydroxy compound.Suitable acids include the oxyacids, for example, phosphoric acid,phosphorus acid, hypophosphorus acid, and the like; phosphorus acidderivatives, for example, acid phosphates, and other relatively strongacids, for example, p-toluenesulfonic acid, trifiuoroacetic acid, andthe pyridine salts of hydrochloric, sulfuric, perchloric,orthophosphoric and trifluoroacetic acids. The reaction is conductedunder substantially anhydrous conditions. In a preferred procedure, theacid catalyst is added to a solution of the 20-hydroxy steroid and thecarbodiimide in the hydrocarbon sulfoxide solvent or solvent mixture.They are then maintained together within the cited temperature range.Upon the completion of this reaction, the product compound of thepresent invention (V) is obtained.

Alternatively, the 20-hydroxy compound can be oxidized to the product(V) with chromium trioxide in tertiary amine solvent, such as pyridine,lutidine, and the like. This reaction is preferably conducted at orabout room temperature for from 12 to 24 hours. During this oxidationprocedure, hydroxyl groups at C16oc and C- 170:, if present, areprotected by conventional acylation or the formation of acycloalkylidenedioxy derivative. These can be removed later, if desired,upon conventional hydrolysis.

Besides being prepared from 16a-hydroxyl or acyloxy or16a,l7ot-cycloalkylidenedioxy-containing starting materials, the finalproducts of the present invention containing these 16-substituents canalso be prepared, in certain cases, from a l6-desoxy-20-ol (III), al6-desoxy-A 20-01 (IV), or a 16-desoxy-A -20-one (V). This isaccomplished by first incubating with Streptomyces roseochromogenus,thereby giving the corresponding L-Ol of the respective startingsteroid.

Esterification of the loehydroxyl group follows by conventionalprocedures, such as by reacting with an acid chloride or anhydride, forexample, one corresponding to the carboxylic acids mentionedhereinabove, in pyridine, or the like, at room temperature for fromabout 12 to about 24 hours. In those instances when it is desired tosimultaneously acylate a l7a-hydroxyl group, if present, the160:,17ot-di01 is reacted with a mixture of an acid anhydride and thecorresponding acid in the presence of a strong acid catalyst, forexample, p-toluenesulfonic acid, or the like, at room temperature forfrom about 12 to 24 hours.

Similarly, by reacting a l6a,17 x-diol (III), (IV) or (V) with analdehyde or ketone in the presence of a strong acid catalyst in themanner described in U.S. Pat. No. 3,048,481, the corresponding16a,17m-cycloalkylidenedioxy derivative is obtained.

When preparing 16-methyl-l9-nor derivatives, the 16- methyl-19-norstarting materials (I) can be obtained in the manner described in U.S.Pat. No. 3,065,228. In this method 16(0: or,8)-methyl-19-hydroxypregnenolone or 16(a orB)-methyl-17a,l9-dihydroxypregnenolone is first oxidized to give thecorresponding l6'(o or B)-methyl- A -pregnen-l'9-(ol, one or oicacid)-3,20-dione or 16(oc or 3)-methyl-A -pregnen-1704-01-19-(ol, one oroic acid)- 3,20-dione. The oxygenated 1OB-methyl group of the thusformed derivative is then eliminated or decarboxylated by conventionalprocedures thus giving 16(oc or ,B)-methyl-l9-norprogesterone (I; R andR =hydrogen, T=methyl) or 16(a or8)-methyl-19-norpregn-4-en-17a-ol-3,20- dione (I; R=hydrogen, R'=hydroxy, T=methyl). The latter can then be esterified at thel7-position, if desired, in the manner described hereinabove.

An illustrative but by no means exhaustive listing of3,20-diketo-4-oxa-A -5aand 5 3-pregnenes falling within the scope ofFormula V hereinabove which can be prepared by the above-illustratedprocess includes: 4-oxa-5a-pregn-1-ene-3,ZO-dione.4-oxa-5fi-pregn-1-ene-3,20-dione,4-oxa-19-nor-5a-pregn-1-ene-3,20-dione, 4-oxa-19-nor-58-pregn-1-ene-3,20dione, 4-oxa-Su-pregn-1-en-17x-ol-3,20-dione,4-oxa-17ot-acetoxy-5ot-pregn-l-ene-3,20-dione,4-oxa-l7a-acetoxy-5fi-pregn-1-ene-3,20-dione,4-oxa-17a-acetoxy-19-nor-5m-pregn-4-ene-3,ZO-dione,4-oxa-17u-acetoxy-19-nor-5fi-pregn-4-ene-3,20-dionc,4-oxa-5B-pregn-1-en-l7a-ol-3,20-dione,4-oxa-17a-propionoxy-5fl-pregn-1-ene-3,20-dione,4-oxa-l7owbutyryloxy-19-nor-5ot-pregn-1-ene-3,20-dione, 4-oxa-19-nor-5a-pregn-l-en- 17 OL-O1-3,20-dlOIl,4-oxa-19-nor-5B-pregn-1-en-l7m-ol-3,20'-dione,4-oxa-l7a-caproyloxy-19-nor-55-pregn-1-ene-3,20-dione,4-oxa-16a-methy1-5ot-pregn-1-ene-3,20-dione, 4-oxa-1 Ga-methyI-SB-regn-1-ene-3 ,20-dione, 4-oXa-16B-methyl-SB-pregn-1-ene-3,20 dione,4-oxa-1Get-methyl-19-nor-5a-pregn-1-ene-3,20-dione,4-oxa-l6B-methyl-l9-nor-5ot-pregn-1-ene-3,20-dione, 4-oxa-1fin-methyl-19-nor-5 3-pregn-1-ene-3 ,20-dione,4-oxa-165-methyl-l9-nor-5p-pregn-1-ene-3,20dione-,4-oxa-16a,17ot-diacetoxy-5u-pregn-1-ene-,20-dione,4-oxa-5,B-pregn-1-ene-l6a,l7a-diol-3,20-dione,4oxa-16a,17u-diacetoxy-5fi-pregn-1-ene-3,20-dione,4-oxa-19-nor-5or-pregn-1-ene-16a,17u-diol-3,20-dione,4-oxa-16a,17x-diacetoxy-l9-nor-5a-pregn-1-ene-3,20-

dione, 4-oxa-19-nor-5fl-pregn-1-ene-16a,17a-diol-3,20-dione,4-oxa-16a,l7a-diacetoxy-19-nor-5p-pregn-1-ene-3,20-

dione, 4-oxa-16a,17a-isopropylidenedioxy-Set-pregn-1-ene- 3,20-dione,4-oxa-16 a, 17a-isopropylidenedioxy-SB- regn- 1 -ene- 3,20-dione,4oxa-16a,17u-isopropy1idenedioxy-19-nor-5ot-pregn- 1-ene-3,20-dione,4-oxa-16a,17a-isopropylidenedioxy-19-nor-5B-pregn- 1-ene-3,20-dione,4-oxa-16m-methyl-5u-pregn-l-en-l7a-ol-3,20-dione,4-oxa-1Ga-methyl-l7u-acetoxy-5u-pregn-1-ene-3,20-

dione, 4-oxa-16a-methyl-17a-acetoxy-5fl-pregn-1-ene-3,20-

dione, 4-oxa-16u-methyl-17a-acetoxy-19-nor-5wpregn-l-ene- 3,20-dione,4-oxa-16a-methyl-17a-acetoxy-l9-nor-5fl-pregn-l-ene- 3,20-dione,4-oxa-16/3-methyl-5u-pregn-1-en-17a-o1-3,20-dione,4-oxa-1Gfi-methyl-17u-propionoxy-5a-pregn-1-ene- 3,20-dione,4-oxa-16ot-methyl-5B-pregn-1-en-17a-o1-3,20-dione,4-oxa-1Got-methyl-17a-butyryloxy-5fl-pregn-1-ene-3,20-

dione, 4-oxa-16fi-methyl-5fi-pregn-1-en-17a-o1-3,20'-dione,4-oxa-16fl-methyl-17a-caproy1oxy-5fl-pregn-1-ene-3,20

dione, 4-oxa-16a-methyl-19-nor-5a-pregn-1-en-17a-ol-3,20-

dione,4-oxa-16at-methyl-17a-fi-chloropropionoxy-19-nor-5apregn-1-ene-3,20-dione,4-oxa-16fl-methyl-19-nor-5a-pregn-1-en-17a-ol-3,20-

dione, 4-oxa-16fl-methyl-17a-cyclopentylpropionoxy-19-nor-Set-pregn-1-ene-3,20-dione,

4-oxa-l6a-methyl-19-nor-5fl-pregn-1-en-l7a-ol-3,20-

dione,

4-oxa-16ot-methyl-l7oc-heptanoyloxy-l9-nor-5B-pregn- 1-ene-3,20-dione,

4-oxa-16B-methyl-19-nor-55-pregn-1-en-17u-ol-3,20-

dione,

4-0): a- 1 6B-methyl-17a-trimethylacet0xy-19-nor-5B-pregn-1-ene-3,20-dione.

The following examples serve to further typify the manner by which thepresent invention can be practiced but, as such, should not be construedas limitations upon the overall scope hereof.

EXAMPLE 1 A solution of 5.2 grams of progesterone, 50 cc. of glacialacetic acid and 50 cc. of ethyl acetate, contained in an ozonation tube,is cooled in an acetone-Dry Ice bath to about C. At this point, a streamof ozone (0.024 mole/hour) is passed through the solution for two hours,following which 20 cc. of water and 3 cc. of an aqueous 30% hydrogenperoxide solution are added, with vigorous stirring. The resultingmixture is stirred for 17 hours at room temperature and then allowed tostand at room temperature for 48 hours. Following this reaction period,the solution is concentrated to a small volume under reduced pressure ona steam bath, then diluted with 20 cc. of methanol and poured intowater. The thus obtained mixture is extracted with diethyl ether, andthe resulting extracts are washed with water, then dried over sodiumsulfate and evaporated to dryness. The resulting residue ischromatographed on 250 grams of alumina to obtain the3,5-secopregnane-5,20-dion-3-oic acid product.

This procedure is repeated in every detail except progesterone isreplaced by 19-norprogesterone,

pregn-4-en- 17 a-o1-3 ,20-dione, 17a-acetoxypregn-4-ene-3,20-dione,19-11orpre gn-4-en- 17a-ol-3,20-dione,l7ot-acetoxy-19-norpregn-4-ene-3,ZO-dione, 1604-11161211YlPIgfl-4-6116-3,20-dione, 16B-methylpregn-4-ene-3 ,20-dione,16a-methyl-19-norpregn-4-ene-3,20-dione,16,8-methyl-19-norpregn-4-ene-3,20-dione,16a,17a-ethylidenedioxypregn-4-ene-3,20-dione, 1 60a, 17a-isopropylidenedioxyp re gn-4-ene-3 ,ZO-dione, 16a,17 x-.(1'-phenylethylidenedioxy)-pregn-4-ene- 3,20-dione,16a,17a-isopropy1idenedioxy-19-norpregn-4-ene-3,20-

dione, 16a-methylpregn-4-en-17a-ol-3,20-dione,1u-methyl-17u-propionoxypregn-4-ene-3,20-dione, 16B-methylpre gn-4-en-17 OL-O1-3,20-dl0116, 16,8-methyl-17a-butyryloxypregn-4-ene-3 ,ZO-dione,16m-n1ethyl-19-norpregn-4-en- 1711-01-3 ,20-dione,16a-metl1yl-l7a-caproyloxy-19-norpregn-4-ene-3,20-

dione, 16,8-methyl-19-norpregn-4-en-17u-ol-3 ,20-dione, and16,B-methyl-17ot-heptanoyloxy-19-norpregn-4-en-17u-ol- 3,20-dione,

respectively. In each case, the corresponding 3,5-seco-5- on-3-oic acid,namely,

19-nor-3,5-secopregnane-5,20-dion-3-oic acid,

3,5-secopregnan-17a-o1-5,20-dion-3-oic acid,

3,5 -seco-17 a-acetOXypregnane-S ,20-dion-3-oic acid,

19-nor-3,5-secopregnan-l7ot-ol-5,20-dion-3-oic acid,

17a-acetoxy-19-nor-3,S-secopregnane-5,20-dion-3-oic acid,

16a-methyl-3,5-secopregnane-5,20-dion-3-oic acid,

16B-methyl-3,5-secopregnane-5,20-dion-3-oic acid,

16u-methyl-l9-nor-3,5-secopregnane-5,20-dion-3-oic acid,

-methyl-19-nor-3,5-secopregnane-5,20-dion-3-oic acid,

1601,17 ot-ethylidenedioxy-3,S-secopregnane-5,20-dion-3- oic acid,

7 16a,17ot-isopropylidenedioxy-3,5-secopregnane-5,20-

dion-3-oic acid, 16a,l7ot-(1-phenylethylidenedioxy) -3,5-secopregnane-5,20-dione-3-oic acid,16a,l7a-isopropylidenedioxy-19-nor-3,5-secopregnane- 5,20-dion-3-oicacid, 16ot-methyl-3,S-secopregnan-l7a-ol-5,20-dion-3-oic acid,16u-methyl-17a-propionoxy-3,5-secopregnane-5,20-

dion-3-oic acid, 16,8-rnethyl-3,5-secopregnan-17u-o15,20-dion-3-oicacid, l6fl-methyl-17a-butyryloxy-3,5-secopregnane-5,20-

dion-3-oic acid, l6ot-rnethyl-19-nor-3,S-secopregnan-17ot-ol-5,20-dion-3-oic acid, 16a-methyl-17a-caproyloxy-19-nor-3,5-secopregnane-5,20-dion-3-oic acid,16,8-methyl-l9-nor-3,5-secopregnan-17a-ol-5,20-dion- 3-oic acid, and16B-methyl-17a-heptanoyloxy-l9-nor-3,5-secopregnane- 5,20-dio11-3-oicacid products, respectively, is obtained.

EXAMPLE 2 An aqueous sodium periodate solution was prepared bydissolving 20 grams of sodium periodate in 250 cc. of water.

To a solution of 5 grams of progesterone in 300 cc. of an azeotrophicmixture of t-butanol and water there is added, with stirring, a solutionof 2.8 grams of potassium carbonate in 80 cc. of water, followed by 50cc. of the above-prepared sodium periodate solution and 5 cc. of an 0.8%solution of potassium permanganate in water. Next, the remainder of thesodium periodate solution is added in small portions, with furtheramounts of the potassium permanganate solution also being added asnecessary to maintain the characteristic color.

Following the addition of the last of the sodium periodate solution, theresulting reaction mixture is allowed to stand at room temperature fortwo hours, then ad mixed with aqueous sodium bisulfite solution todestroy excess potassium permanganate, and finally concentrated to avolume of 400 cc., cooled to 4 C., acidified with icecold aqueous 50%sulfuric acid and extracted with methylene dichloride. The thus obtainedextract is washed with an aqueous sodium bisulfite solution until freeof iodine, then with water until neutral, and then dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Theresultant residue is chromatographed on silica gel to obtain the3,5-secopregnane-5,20- dion-3-oic acid product.

EXAMPLE 3 A solution of 1 gram of sodium borohydride in 3 cc. of wateris added to an ice-cold solution of 1 gram of3,5-secopregnane-5,20-dion-3-oic acid in 120 cc. of

dioxane, and the resulting reaction mixture is allowed to stand for 16hours at C. Following this reaction period, the reaction mixture isadjusted to pH 1 by the addition of 6 N hydrochloric acid (this alsoserves to decompose the excess sodium borohydride present) and theresulting precipitate is collected by filtration to obtain a mixture of4-oxa-5a-pregnan-2()ut-o1-3-one, 4-oxa-5fl-pregnan-20otol-3-one, 4oxa-5ot-pregnan-20B-ol-3-one, and 4-ox-a-5flpregnan-B-ol-3-one products.The mixture is then separated into the individual isomers bychromatography on alumina followed by individual recrystallization fromacetone hexane.

By repeating this procedure using the remaining 3,5- sec-5-on-3-oic acidproducts prepared as described in Example 1 hereinabove as the steroidstarting materials, the corresponding 4-oxa-5(ot and [3)pregnan-20(a and,8) ol-3-ones, namely, 4-oxa-19-nor-5(a and fi)pregnan20(u andfi)ol-3-one, 4-oxa-5 (or. and ,B)pregnane-l7a,20(a and [3)diol-3-one,

4-OXa-170t-21CtOXy-5(Ot and {3) pregnan-20(ot and B)- 3-one,

4-oxa- 1 9-nor-5(u and {3) pregnane-17ot,20 (a and ,6) diol- 3-one,

4-oxa-17a-acetoxy-l9-nor-5 (0c and ,B)pregnan-20 (oz and 3) ol-3-one,

4-oxa-16ot-methyl-5 (on and fl)pregnan-20(tx and 8)01- 3-one,

4-oxa-l6a-methyl-19-nor-S (a and [3) pregnan-20(u and p) ol-3-one,

4-oxa-l6fl-methyl-l9-nor-5 (a and ,8)pregnan-20(a and 13) ol-3-one,

4-oxa- 1 6oz, l7oc-ethYlideI1eCllOXY-5 a and ,B) pregnan-20 (cc and{3)01-3-one,

4-oxa-16a,17u-isopropylidenedioxy-5(a and 5) pregnan- ZO-(u and [3)ol-3-one,

4-oxa-16u,17a-(1'-pheny1ethylidenedioxy)-5(a and 3) pregnan-20( x andB)ol-3-one,

4-oxa-16a,l7a-isopropylidenedioxy-19-nor-5(a and ,3)

pregnan-20(a and (3)01-3-one,

4-oxa-l6a-rnethyl-5 (a and ;3)pregnane-17a,20(a and ,8)

diol-3-one,

4-oxa-l6oz-methyl-17a-propionoxy-5 (a and B)pregnan- 20(a and 5)ol-3-one,

4-oxa-16fl-methyl-5 (a and fi)pregnane-17a,20(a and 5) diol-3-one,

4-oxa-16fl-methyl-17ot-butyryloxy-5(a and fl)pregnan- 20(a and,B)ol-3-one,

4-oxal 6a-methyl-19-nor-5(ot and [3) pregnane- 17OL,20( 0c andB)diol-3-one,

4-oxa-16a-methyl-17zx-caproyloxy-19-nor-5-(a and pi) pregnan-20(a andfi)ol-3-one,

4-oxa-l Gfi-methyl- 19-nor-5 (a and 5) pregnane- 1704,20 (a andfl)diol-3-one, and

4-oxa-l6fl-methyl-17a-heptanoyloxy-19-nor-5 (0c and 3) pregnan-20(a andfi)ol-3-one products, respectively, are obtained and then separated intothe individual isomers by chromatography on alumina followed byindividual recrystallization from acetone:hexane.

EXAMPLE 4 A mixture of 350 mg. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 10 cc. of dioxane and 500 mg. of 4-oxa-5a-pregnan-20a-ol-3-one is refluxed for hours. Following this reactionperiod, the reaction mixture is cooled to room temperature, filtered toremove the 2,3-dichloro- 5,6-dicyano-1,4-benzohydroquinone formed duringthe reaction, and the filtrate then evaporated to dryness. Next, the dryresidue is dissolved in acetone and filtered through 10 grams ofalumina, following which the filtrate is evaporated to dryness. Theresulting residue is crystallized from acetonezhexane to obtain4-oxa-5a-pregn-1-en-20aol-3-one product.

By repeating this procedure using the remaining 4-oxa- 5(oc andfi)pregnan-20(a and 3)ol-3-ones prepared as described in Example 3hereinabove, the corresponding A steroids, namely,

9 4-oxa-17a-acetoxy-19-nor-5fl-pregn-I-en-ZOa-oLB-one, 4-oxa-17a-acetoxy- 1 9-nor-5 arpregn- 1-en-20 3-ol-3one,4-oxa-17a-acetoxy-19-nor-5B-pregn-1-en-20B-0l-3-or1e, 4-oxa-16a-methyI-Sa-pregn-1-en-20a-o1-3-one,4-oxa-l6ot-methyl-5fi-pregn-1-en-20oz-o1-3-0ne,4-oxa-16a-methyl-5a-pregn-1-en-2OB-ol-3-one, 4-oxa-l 6a-methyl-5B-pregnl-en-20,B-ol-3-one, 4-oxa-16fi-methyl-5a-pregn-l-en-20a-ol-3-one, 4-oxa-1 6B-methyl-5fl-pregnl -61'120oL-O13-0l'1, 4-ox-al 6fi-met hyl-5u-pregn-1 -en-/8-ol-3-one, 4-oxa-16 8-methy1-5B-pregn-1-en-20f3-ol-3-one,4-oxa-l 6a-methyl-l9-nor-5a-pregn-1-en-20a-ol-3-one, 4-oxa-l6a-methyl-l9-nor-5fl-pregn-1-en-20a-o1-3-one,4-oxa-l6a-methyl-19-nor-5a-pregn-1-en-20fl-ol-3-one,4-oxa-16a-methyl-l9-nor-5/3-pregn-1-en-20fi-ol-3-one,4-oxa-16fl-methyl-l9-nor-5a-pregn-1-en-20z-ol-3-one,4-oxa-16fi-methyl-19-nor-Sfl-pregn-1-en-20a-ol-3-one,4-oxa-16B-methyl-19-nor-5u-pregn-1-en-205-ol-3-one,4-oxa-1GB-methyl-19-nor-5fi-pregn-l-en-20fi-ol-3-one, 4-oxa-16'a, l7a-ethylidenedioxy-Six-pregn-1-en-20a-ol- 3-one,

4-oxa-1 6a, 17 a-ethylidenedioxy-5 fi-pregn- 1-en-20oc-ol- 3-one,

4-oxa-16a, 17 a-ethyIidenediQXy-S aapregn- 1-en-205-0l- 3 -one,

4-oxa-16u,17a-ethylidenedioxy-SB-pregn-1-en-20,B-o1- 3-one,

4-oxa-16a,17a-isopropylidenedioxy-Soc-pregn-Len-20aol-3-one,

4-oxa-16a,17a-isopropylidenedioxy-Sfl-pregn-Len-20aol-3-one,

4-oxa-16a,17a-isopropylidenedioxy-Set-pregn-Len-2018- ol-3-one,

4-oxa-16u, 17a-isopropylidenedioxy-SB-pregn-Len-20po1-3-one,

4-oxa-1 6a,17a-( 1-pheny1ethylidenedioxy) -5u-pregn- 1-en-20a-ol-3-one,

4-OXa-16u,17oc-( 1-phenylethy1idenedioxy)-5,B-pregn- 1-en-20u-ol-3-one,

4-oxa-16u, l7oc- 1'-pheny1ethylidenedioxy) -5a-pregn- 1-en-20p-ol-3-one,

4-OXa-16oz,17oc-( 1-phenylethylidenedioxy -5,B-pregn-1-en-20fl-ol-3-one,

4-oxa-16a,17a-isopropylidenedioxy-19-nor-5a-pregn- 1en-20a-ol-3-one,

4-oxa-16a-17a-isopropylidenedioxy-19-nor-5B-pregnl-en-20a-ol-3 -one,

4oxa-16a,17a-isopropylidenedioxy-19-nor-5a-pregn- 1-en-20 fl-ol-3-one,

4-oxa-16a,17a-isopropy1idenedioxy-19-nor-5/3-pregn- 1-en-20,B-ol-3-one,

4-oxa- 1 6a-methyl-5u-pregn-1-ene- 170:,20a-di01-3-0116,

4-oxa-1 6 u-methyI-SB-pregnl-ene- 17a,20a-di01-3-0116,

4-oxa-1 6a-methyl-5a-pregn-1-ene-17a,205-diol-3-one,

4-oxa-16a-methyl-5fi-pregn-1-ene-17u,20;8-diol-3 -one,

4-oxa-16a-methyl- 17a-propionoxy-5oc-pregn-1-en-20aol-3-one,

4-oxa-16a-methyl-17u-propionoxy-5a-pregn-Len-20,3-

ol-3 -one,

4-oxa-16a-methyl-l7u-propionoxy-SIR-pregn-l-en-ZOfio1-3-one,

4-oxa- 1 6,8-methyl-5 u-pregn-l-ene-17 0:,20oc-di0l-3-OI18,

4-oxa-16B-methyl-5fi-pregn-l-ene-17a,20a-diol-3-one,

4-oxa-16fi-methyl-5a-pregn-1-ene-17a,20B-diol-3-one,

4-oxa- 16;8-n1ethy1-17a-butyryloxy-5a-pregn-Len-20ao1-3-one,

4-oxa-1 GB-methyl- 17 a-butyry1oxy-5B-pregn-l-en- 17 41,20 0:-

ol-3-one,

4-oxa-16,3-methyl-17a-butyryloxy-5u-pregn-Len-17a- 20 8-ol-3-one,

1 0 4-oxa-16a-methyl-19-nor-5u-pregn-l-en-17a,20a-o1- 3 -one,4-oxa-16a-methyl- 19-nor-5B-pregn-1-en-l7a,2()a-ol- 3-one,4-oxa-16a-methyl-l9-nor-5a-pregn-1-en-17a,20/3-o1- 3-one,4-oxa-16a-methyl-19-nor-5fi-pregn-l-en-1711,205-01- 3 -one,4-oxa-1Got-methyl-17a-caproyloxy-19 nor-5a-pregn-l-en- ZOa-Ol-3 -one,4-oxa-16a-methyl-17a-caproyloxy-19-nor-5/3-pregn-l-en- 17a,20a-o1-3-one, 4-0Xa-lGoa-methyl-l7a-caproyloxy-19-nor-5a-pregn-1-en-17a,20;8-o1-3-one,4-oxa-l6u-methyl-17a-caproyloxy-l9-nor-5/8-pregn-l-ene- 17oc,20fl-dl0l-3-OI16, 4-oxa-168-methy1-19-nor-5a-pregn-1-en-17u,20o-ol-3- one, 4-oxa- 16,8-methy1-19-nor-5fl-pregn- 1-611l71x,20a-Ol-3- one,4-oxa-16fl-methyl-19-nor-5a-pregn-1-en-l7a,20a-ol-3- one, 4-oxal6,6-methyl- 1 9-nor-5 fi-pregn- 1-en- 17 0:,2011-01-3- one,4-oxa-16B-methyl- 17a-heptanoyloxy-l9-nor-5a-pregn-1- en-20a-ol-3-one,4-oxa-l6B-methyl-19-nor-5a-pregn-1-en-17u,20;8-ol-3- one,4-oxa-1GB-methyl-l7a-heptanoy1oxy-19-nor-5a-pregn-1-en-17a,20a-ol-3-one,4-oxa-16fl-methyl-17a-heptanoyloxy-19-nor-5B-pregn-1- en-17,20x-ol-3-one, 4-oxa-l6 3-methyl-17a-heptanoyloxy-l9'-nor-5a-pregn-1-en-17a,20/8-ol-3-one, and 4oxa- 1 613-methyl-l7a-heptanoyloxy- 1 9-nor-55-pregn- 1-6l1-17oc,20}3-0l-3-0Il6 products, respectively, are obtained.

EXAMPLE 5 A substantially anhydrous solution is prepared by dispersing0.3 mmole of 4-oxa-5a-pregn-1-en-20a-ol-3-one and 0.9 mmole ofN,N'-dicyclohexylcarbodiimide in 1.5 ml. of dimethylsulfoxide. To theresultant solution is added 0.15 mmole of substantially anhydroustrifluoroacetic acid. The resulting reaction mixture is maintained atroom temperature for two hours with stirring and then an additional 0.3mmole of substantially anhydrous N,N'- dicyclohexylcarbodiimide is addedthereto. The reaction mixture is then allowed to stand at roomtemperature for three hours and an additional 0.3 mmole of substantiallyanhydrous N,N-dicyclohexylcarbodiimide is added. The reaction mixture isthen allowed to stand at room temperature for another hour and is thenevaporated to dryness under vacuum. The resulting residue is separatedby thin layer chromatography on Silica G in the system chloroform:ethylacetate (4:1), eluting with methanol, to obtain the4-oxa-5a-pregn-1-ene-3,20-dione product.

By repeating this procedure using the remaining 4- oxa-5(a andfi)pregn-1-en-20(u and ,B)ol-3-ones prepared as described in Example 4hereinabove, the corresponding 3,20-dione products are obtained, thatis, 4oXa-5fl-pregn- 1-ene-3,20-dione,4-oxa-19-nor-5a-pregn-1-ene-3,20-dione,4-oxa-l9-nor-5fl-pregn-1-ene-3,20-dione, 4-oXa-5u-pregn-4-en-l7a-ol-3,20-dione, and so forth.

Alternatively, the oxidation can be conducted as follows:

One gram of 4-oxa-5a-pregn-1-en-20o-ol-3-one is dissolved in 20 cc. ofpyridine and then added to a mixture of 1 gram of chromium trioxide in20 cc. of pyridine. The resulting reaction mixture is allowed to standat room temperature overnight. Following this reaction period, thereaction mixture is diluted with ethyl acetate and filtered throughCelite. The filtrate is thoroughly washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. The resultingresidue is crystallized 1 1 from acetonezhexane to obtain the4-oxa-5a-pregn-1-ene- 3,20-dione product.

EXAMPLE 6 A mixture of 1 gram of 4-oxa-5a-pregn-1-en-l7u-ol- 3,20-dione,50 cc. of acetic acid, 25 cc. of acetic anhydride and 1 gram ofp-toluenesult'onic acid monohydrate is allowed to stand at roomtemperature for 24 hours. Following this reaction period, the reactionmixture is poured into water and stirred until excess acetic anhydridehydrolyzes. The product is extracted with methylene dichloride. The thusobtained extract is washed with water until neutral, then dried overanhydrous sodium sulfate and evaporated to dryness. The resultingresidue is crystallized from acetone:diethyl ether to obtain the 4-oxa-17a-acetoxy-5a-pregn-1-ene-3,20-dione product.

By repeating this procedure using 4-oxa-5B-pregn-1-en-17a-o1-3,20-dione,4-oxa-1'9-nor-5a-pregn-1-en-17u-ol-3,20-dione,4-oxa-19-nor-5fi-pregn-1-en-17u-ol-3,20-dione,4-oxa-16a-methyl-5a-pregn-l-en-17a-ol-3,20-dione,4-oxa-16a-methyl-5/3-pregn-1-en-l7a-ol-3,20-dione,4-oxa-16B-methyl-5a-pregn-1-en-17u-ol-3,20-dione,4-oxa-1Gfi-methyI-Sa-pregn-1-en-17a-ol3,20-dione,4-oxa16B-rnethyl-5/3-pregn-l-en-l7a-ol-3,20-dione,4-oxa-16ot-rnethyl-l9-nor-5ot-pregn-l-en-l7a-ol-3,20-

dione, 4-oxa-1Got-methyl-19-nor-5/3-pregn-1-en-17a-o1-3,20-

dione, 4-0xa-16B-methyl-19-nor-5a-pregn-1-en-17 tat-016,20-

dione, 4-oxa-1Git-methyl-l9-nor-5fi-pregn-1-en-17a-ol-3,20-

dione, respectively, as the steroid starting materials, thecorresponding 17-acetate products are obtained.

Similarly, by using each of the free 17a-ols mentioned above as thesteroid starting material, and replacing the mixture of acetic acid andacetic anhydride with mixtures of propionic acid and propionicanhydride, cyclopentylpropionic acid and cyclopentylpropionic anhydride,caproic acid and caproic anhydride and enanthic acid and enanthicanhydride, respectively, the corresponding 17- propionates,-cyclopentylproprionates, -caproates and -enanthates are obtained.

Similarly, by using each of thef ree 17a-ols mentioned above as thesteriod starting material, and replacing the mixture of acetic acid andacetic anhydride with mixtures of propionic acid and propionicanhydride, cyclopentylpropionic acid and cyulopentylpropionic anhydride,caproic acid and caproic anhydride and enanthic acid and EXAMPLE 7 Aculture of Streplomyces roseochromogenus, ATCC No. 3347, is prepared inan inclined agar medium containing 1% by weight of glucose and 1% byWeight of yeast extract, each of these percentages being based on thetotal weight of said agar medium. A number of 250 cc. of Erlenmeyerflasks, each containing 50 cc. of a sterilized aqueous medium containing2% by weight of peptone and by Weight of corn syrup, said percentagesbeing based on the total weight of said aqueous medium, are theninoculated with 1 cc. of a suspension of the above-prepared culture, andthe resulting mixtures are then incubated with aeration and agitation,at 28 C. for 48 hours. This gives a vegetating, growing culture ofStreptomyces roseochromogenus.

Next, 10 mg. of 4-oxa-5a-pregn-1-en-17a-o1-3,20-dione are added to eachflask and the resulting mixtures are stirred for 72 hours at roomtemperature with aeration. Following this incubation period, theincubated mixtures are combined and extracted with methylene dichloride.The thus obtained extracts are washed with water, dried over anhydroussodium sulfate, filtered and evaporated to dryness under reducedpressure. The resulting residue is pregn-1-ene-16a,17ot-diol-3,20-dioneproduct.

12 This procedure is then repeated in every detail except 4-oxa-53-pregn-l-en-17a-ol-3,20 dione, 4-OXa-19-I10f-5OL-pregn-l-en-17a-ol-3,20-dione, and 4-oxa-l'9-nor-5 3-pregn-1-611-17u-0l-3,20-d10116, respectively, are used as the steroid startingmaterials. In each case, the corresponding 16u-hydroxy steroid productis obtained.

EXAMPLE 8 The procedure of Example 6 hereinabove is again repeated usingeach of the 16a-hydroxy steroids prepared as described in Example 7hereinabove as the steroid starting material to obtain the4-oxa-16a,l7u-diacetoxy-5a-pregnl-ene-3,20-dioue, 4 oxa16a,17a-diacetoxy-5fl-pregn-1- ene-3,20-dione,4-oxa-16a,17a-diacetoxy-19-nor-5ot-pregnl-ene-3,20-dione, and4-oxa-l6a,17a-diacetoxy 19 nor- 5 fi-pregn-1-ene-3,20-di0ne,respectively.

What is claimed is:

1. The compound represented by the formula:

wherein R is hydrogen or methyl; R is hydrogen, hydroxy or hydrocarboncarboxylic acyloxy containing less than 12 carbon atoms, T is hydrogen,tit-hydroxy, a-hydrocarbon carboxylic acyloxy containing less than 12carbon atoms, u-methyl or fi-methyl, with T being other than ozhydroxyor tit-hydrocarbon carboxylic acyloxy when R is hydrogen, and R and Ttaken together represent the grouping wherein R is alkyl of up to eightcarbon atoms or monocyclic aryl of six to eight carbon atoms, and R ishydrogen or alkyl of up to eight carbon atoms, provided that when eachof R and T is hydrogen, then R is hydrogen.

2. The compound claimed in claim 1 wherein R is hydrogen, hydroxy oracetoxy, and T is hydrogen or amethyl, and R and T taken together isisopropylidenedioxy.

3. The compound claimed in claim 1 wherein R is hydroxy and T ishydrogen.

4. The compound in claim 1 wherein R is acetoxy and T is hydrogen.

5. The compound claimed in claim 1 wherein R is hydrogen and T isa-methyl.

6. The compound claimed in claim 1 wherein R is hydroxy and T isa-methyl.

7. The compound claimed in claim 1 wherein R is acetoxy and T isa-methyl.

8. The compound claimed in claim 1 wherein R and T taken together isisopropylidendioxy.

References Cited UNITED STATES PATENTS 3,413,311 11/1968 Cross 260340.5

3,417,106 12/1968 Cross 260-340 .5

FOREIGN PATENTS 6503543 9/ 1965 Netherlands 260-3403 ALEX MAZEL, PrimaryExaminer I. H. TURNIPSEED, Assistant Examiner U.S. Cl. X.R.

ammo STATES PATENT @FFECE CERTEMCATE Cl CCECTWN Patent No. 3 4 421 DatedFebruary 22 1972 I nvent0r(s) Alexander D. Cross It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

. Column 2, line 4, after "pionate," and before "aminoacetate, caproate,enan" delete B-chloropropionate,

Column 2, line 8, "claim" should be claims Column 2, line 64, (which cana contain trace or larger amounts of acetic" should be (which cancontain a trace or larger amounts of acetic I Column 4, line 63', "No.3,048,481, should'be No.- 3,048,581, I

Column 5, between lines 20 and 21, insert 4-oxa-l9-nor-SOL-pregn-l-en-l7OL-ol-3, 20,dione,

Column 5, delete line 22 thereof. 7

Column 5, line 32, "4- oxa-l6oc,l7oL-diacetoxy5oc-pregnl ene,ZO-dione,should be 4fioxa-'-l6on,l70L-diacetoxy-5OLpregn lene3,20-dione,

Column 8, between lines 6 and 7, insert 4-oxa-l6B- methyl-5 (a and B)pregnan20'(OL and B)ol3one,

Column 10, line 21, "lenl7OL,200L-ol3" should be l-enl7OL,2OB-ol3- 7Column 10, line 23, "len-l7oL,20oL-ol3 should be lenl7OL, 203-01-3- 9Column 10, delete lines 27 through BO-thereof.

Column 10, line 32, "enl7,200Lol3-'one,'"should be en-l7QL,2OOL-ol3-one,

Column ll, line 23, "4-oxa-l'6B+methyl50Lpregnlenl70Lol3,20dione" shouldbe 4-oxa-l6Bmethyl-5Bpregnl' enl7OLol3,20-dione,

I Column ll, delete line- 24 thereof. 7

Column ll, delete lines'45 through 50'thereof.

Column ll, lines 74 and 75, after "residue is" and before "pregn-"insert chromatographed on silica gel to obtain the 4ox'a50b FORM P0105)(10459) USCOMM-DC 60376-1 69 Q U.5 GOVERNMENT PRINTING OFFICES 969 O366"334 UNITED STATES PATENT ew'rer @"HHQAE r Dated February 22, 1972Patent; No. 3 9 644 421 Inventor(s) Alexander D. Cross Page --2-- It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column l2 Claim 1, lines 36 through 39, the formula should appear asfollows:

Signed and sealed this 19th day of December 1972..

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOT'ISCHALK Attesting Officer ICommissioner of Paten' USCOMM-DC 60376-P69 a u.s. GOVERNMENT PRINTINGOFFICE: 1969 0-366-33fl FORM PO-105O (10-69)

